Transforming Growth Factor-??(TGF?) controls tissue homeostasis by inhibiting cell cycle progression, inducing differentiation and apoptosis, and maintaining genomic integrity. Secondly, TGF??orchestrates the response to tissue injury and mediates repair by inducing epithelial to mesenchymal transition (EMT), and by increasing cell motility and -invasiveness in a time- and space-limited manner. While tumors escape from TGF?'s homeostatic function early on in their development, many metastatic breast cancers appear to have co-opted the tissue repair function to enhance their invasive/metastatic phenotype. Our core hypothesis is that whether or not a particular tumor cell is capable of successfully establishing a metastasis within a particular foreign microenvironment will depend on TGF[unreadable]?signaling in the tumor cell as well as on the effects of TGF??on the host cells at the secondary site. Using a unique model of metastatic breast cancer developed by Dr. Kang, Specific Aim 1 will determine whether or not the anti-metastatic efficacy of TGF??pathway inhibitors is a function of the type of metastasis. Specific Aim 2 will determine whether the ability of mammary carcinoma cell lines to successfully establish metastases is predominantly dependent on TGF??actions on the mammary carcinoma cells themselves (so called cell autonomous effects), while Specific Aim 3 will determine the role of TGF??actions on host cells in this process. Finally, as the two major classes of TGF??pathway antagonists (macromolecules that act as ligand traps and chemical kinase inhibitors) have distinct biological and pharmacological properties, Specific Aim 4 will address the question whether and how these differences affect their therapeutic efficacy in metastatic breast cancer. Thus, the global goal of this project is two-fold: (1) The first is the fundamental one of dissecting the roles of TGF??and TGF?/Smad signaling play in the complex symbiotic relationship between a putative metastatic breast cancer cell and the metastatic niche at different secondary sites. (2) The second is the more translational goal of assessing the relative therapeutic merits of the different classes of TGF??pathway antagonists that are being developed for clinical use, with the intent of informing the design of future clinical trials. The proposed studies will have major implications for the health of patients with breast cancer. This is the most common cancer in women, and accounts for the second to highest number of cancer deaths in women. As most of these women die of metastases, elucidating the fundamental mechanisms of breast cancer metastasis and developing novel targeted agents to either treat or prevent metastasis will likely have a major impact on the outcome of women with this disease.